B-Cell lymphomas, such as the B-cell subtype of non-Hodgkin's lymphoma, are significant contributors to cancer mortality. The response of B-cell malignancies to various forms of treatment is mixed. For example, in cases in which adequate clinical staging of non-Hodgkin's lymphoma is possible, field radiation therapy can provide satisfactory treatment. Still, about one-half of the patients die from the disease. Devesa et al., J. Nat'l Cancer Inst. 79:701 (1987).
The majority of chronic lymphocytic leukemias are of B-cell lineage. Freedman, Hematol. Oncol. Clin. North Am. 4:405 (1990). This type of B-cell malignancy is the most common leukemia in the Western world. Goodman et al., Leukemia and Lymphoma 22:1 (1996). The natural history of chronic lymphocytic leukemia falls into several phases. In the early phase, chronic lymphocytic leukemia is an indolent disease, characterized by the accumulation of small mature functionally-incompetent malignant B-cells having a lengthened life span. Eventually, the doubling time of the malignant B-cells decreases and patients become increasingly symptomatic.
While treatment can provide symptomatic relief, the overall survival of the patients is only minimally affected. The late stages of chronic lymphocytic leukemia are characterized by significant anemia and/or thrombocytopenia. At this point, the median survival is less than two years. Foon et al., Annals Int. Medicine 113:525 (1990). Due to the very low rate of cellular proliferation, chronic lymphocytic leukemia is resistant to treatment. Traditional methods of treating B-cell malignancies, including chemotherapy and radiotherapy, have limited utility due to toxic side effects. Using an antibody that binds to a surface component on the B cell is an alternate approach of directing an immune response to cancer cells. The use of monoclonal antibodies to direct radionuclides, toxins, or other therapeutic agents also offers the possibility that such agents can be delivered selectively to tumor sites, thus limiting toxicity to normal tissues. However, antibodies are typically not taken up by cells. Thus, even when an antibody is linked to a toxin, the toxin may only be delivered to the surface of a cell.
A need therefore exists for new agents that can bind to and be internalized within Siglec-expressing cells, including malignant B-cells.
The accumulation of eosinophil leukocytes is a characteristic feature of IgE-mediated allergic reactions such as allergic asthma, rhinitis and eczema. Eosinophil accumulation also occurs in non-allergic asthma. The immediate bronchoconstriction in response to a provoking stimulus in the asthmatic involves mast cell activation and the release of constrictor mediators. This is followed after several hours in some individuals by a late bronchoconstrictor response associated with a massive influx of eosinophils. Repeated provocation results in chronic inflammation in the airways and a marked hyper-responsiveness to constrictor mediators. The magnitude of both the late response and the chronic hyper-responsiveness correlates with the numbers of eosinophils present in the lung.
The global prevalence of asthma continues to increase, affecting millions of peoples' daily lives, but treatment is far from ideal. Clinical responses to current therapies, such as inhaled corticosteroids and leukotriene modifiers are heterogeneous and even with optimal treatment there is a substantial burden of unaddressed disease. Therefore, a need also exists for agents that can control eosinophil-related diseases such as asthma.